MOTS-c is an effective target for treating cancer-induced bone pain through the induction of AMPK-mediated mitochondrial biogenesis

Abstract

Bone cancer pain (BCP), due to cancer bone metastasis and bone destruction, is a common symptom of tumors, including breast, prostate, and lung tumors. Patients often experience severe pain without effective treatment. Here, using a mouse model of bone cancer, we report that MOTS-c, a novel mitochondrial-derived peptide, confers remarkable protection against cancer pain and bone destruction. Briefly, we find that the plasma level of endogenous MOTS-c is significantly lower in the BCP group than in the sham group. Accordingly, intraperitoneal administration of MOTS-c robustly attenuates bone cancer-induced pain. These effects are blocked by compound C, an AMPK inhibitor. Furthermore, MOTS-c treatment significantly enhances AMPKα1/2 phosphorylation. Interestingly, mechanical studies indicate that at the spinal cord level, MOTS-c relieves pain by restoring mitochondrial biogenesis, suppressing microglial activation, and decreasing the production of inflammatory factors, which directly contribute to neuronal modulation. However, in the periphery, MOTS-c protects against local bone destruction by modulating osteoclast and immune cell function in the tumor microenvironment, providing long-term relief from cancer pain. Additionally, we find that chronic administration of MOTS-c has little effect on liver, renal, lipid or cardiac function in mice. In conclusion, MOTS-c improves BCP through peripheral and central synergistic effects on nociceptors, immune cells, and osteoclasts, providing a pharmacological and biological rationale for the development of mitochondrial peptide-based therapeutic agents for cancer-induced pain.

1. Introduction

Bone cancer pain (BCP) is a common clinical symptom of cancer patients, who often experience severe pain without effective treatment [1,2]. Tumors, such as prostate, breast, and lung cancers, have a strong tendency for bone metastasis and bone destruction [1,3]. Mounting evidence has indicated that bone metastasized tumor cells generate pain by releasing inflammatory factors, growth factors, and algogenic substances, which can induce sensitization and activation of the nerve fibers that innervate bone [4–6]. Furthermore, tumor cells can also directly activate sensory nerve fibers, which in turn contribute to peripheral and central sensitization [2,7]. Invasion of bone by tumor cells evokes infiltration of immune cells, including macrophages, T cells and granulocytes, and produces and releases pro-inflammatory mediators (e.g., IL-1β, IL-6, TNF-α, and CCL5), which induce pain by binding to their receptors in sensory neurons [2,8,9]. Although BCP is severe and widespread in patients with advanced tumors, the efficacy of currently available drugs for BCP treatment is limited due to numerous unwanted side effects [1,6]. Therefore, it is necessary to find new therapeutic targets for BCP to improve the quality of life of cancer patients.

MOTS-c, or the mitochondrial open reading frame of 12S rRNA type-c, is a recently discovered mitochondrial-derived peptide [10]. Several recent studies have shown that MOTS-c is involved in the regulation of diabetes [11,12], insulin resistance [10,13], inflammation [14,15], aging [16] and osteoporosis [17,18] through the AMP-activated protein kinase (AMPK) pathway. In particular, AMPK has attracted a great deal of attention as a therapeutic target for the regulation of chronic pain [19–21]. The role of metformin in chronic pain has also been reported to be associated with AMPK activity [22]. Our previous study revealed that a single acute treatment with MOTS-c relieves nerve injury-induced neuropathic pain and inflammatory pain [23,24]. However, due to BCP, the severe pain faced by cancer patients in the late stages of the disease, it is difficult to achieve the desired efficacy of most medications [25], such as pregabalin and celecoxib, for treating neuropathic pain and inflammatory pain.